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In analyzing rate at which psychostimulants enter the brain had been the implications of the similar in vivo efficacy for DAT recognized as an important variable in their reinforcing ef- blockade by cocaine and MP discount 150 mg bupropion amex mood disorder nos icd 9, regarding the low abuse po- fects (7) best 150mg bupropion depression zaps your energy, the relevance of their rate of clearance had not effective 150mg bupropion depression symptoms pdf. Because the rapid- is relevant for understanding their toxicity as it relates to ity of drug effects is an important variable in the reinforcing cerebrovascular disease. The discrepancy could also reflect effects of drugs of abuse (12) and routes of administration the finding that changes in metabolism reflect an average affect drug pharmacokinetics, the results with intravenous of the changes that occur over the uptake period of FDG MP cannot be extrapolated to oral MP. SPECT studies measuring the levels of receptor occupancy by the benzodiazepine drug lorazepam showed that only a few receptors are occupied at pharmacologic doses (13), findings that support the no- CHRONIC EFFECTS OF DRUGS OF ABUSE IN tion that in humans there is a 'reserve' of benzodiazepine THE HUMAN BRAIN receptors. Imaging studies have been done to assess neurochemical Effects on Dopamine Concentration and functional changes in the brain of addicted subjects that are associated with the process of addiction as well as Because the ability of drugs of abuse to increase extracellular changes associated with drug toxicity. Functional imaging DA concentration is considered crucial for their reinforcing strategies have also been used to assess the brain region in- effects, the estimation of DA changes becomes particularly volved in drug-related states such as drug craving. PET and SPECT enable one to carry such mea- Chapter 110. For this purpose, subjects are scanned twice, at baseline and after administration of the drug of abuse, Drug toxicity can be assessed with imaging techniques for and the difference in the binding of the radioligand between brain as well as for other organs. Toxicity from drugs has both conditions is mostly a reflection of drug induced been documented in abusers of cocaine, methamphetamine, changes in extracellular DA. Studies to measure changes in and ecstasy, and the findings from these studies are covered DA concentration induced by drugs of abuse in the human under the subsection of the drug class. In addition, the brain have been carried out for amphetamine, cocaine, and ability to label the drug with a positron emitter and to follow MP (14–16). These studies showed that these three psycho- its distribution in the human body and the availability of stimulant drugs significantly increase extracellular DA, and, radiotracers that allow one to monitor organ function pro- in the case of intravenous MP, the magnitude of drug- vide a mechanism for evaluating potential toxicity of drugs induced DA changes was closely correlated with the inten- to organs other than brain. For example, PET studies done sity of the self-reports of 'high. Cocaine was shown to induce a long-lasting inhibition of the levels of DAT blockade but also of the amount of 18 of the norepinephrine transporter in heart using 6-[ F]flu- DA being released by the terminal (17). Co- caine is a local anesthetic, and its accumulation in heart Effects on Regional Brain Function could result in direct myocardial toxicity. At the same time, inhibition of the norepinephrine transporter by cocaine in- The most widely used imaging approach for the investiga- terferes with a protective mechanism of the heart to remove tion of drugs of abuse has been to assess the effects of acute circulating catecholamines. Thus, these two separate mecha- drug administration on brain glucose metabolism or CBF. Although most Cocaine drugs of abuse decrease regional brain glucose metabolism, Toxicity their effects on CBF are increased by some drugs and de- Studies using PET and-labeled water provided the first creased by others. This discrepancy between metabolism and CBF is probably an indication of the vasoactive proper- documentation of abnormalities in CBF in cocaine abusers Chapter 103: Application of Imaging Technologies in Drug Addiction 1479 cose metabolism are not as pronounced and vary signifi- cantly as a function of detoxification. Also different from the patchy distribution of the CBF defect are the decrements in metabolism that tend to localize to cortical projections of the DA system. In recently detoxified cocaine abusers (less than 1 week), brain glucose metabolism was reported to be significantly higher in orbitofrontal cortex and in stria- tum than in control subjects (28). Metabolic activity was highest in subjects tested during the initial 72 hours after withdrawal, and cocaine abusers who had the highest brain metabolic values had also the highest subjective ratings for craving. In contrast, cocaine abusers tested between 1 and 4 months of detoxification showed significant reductions in metabolic activity in prefrontal cortex, orbitofrontal cor- tex, and anterior cingulate gyrus (Fig. Thus, the orbitofrontal cortex, which is hypermetabolic during early cocaine discontinuation, becomes hypometabolic with protracted cocaine withdrawal. In addition to the studies measuring resting metabolism FIGURE 103. Brain images obtained with PET and [15O]water or CBF, the effects of pharmacologic challenges in cocaine to measure cerebral blood flow in a cocaine abuser. Cerebral blood flow in chronic caine was found to reduce brain glucose metabolism in cor- cocaine users: a study with positron emission tomography. Br J tical and subcortical brain regions as measured by FDG Psychiatry 1988;152:641–648, with permission. In contrast, an fMRI study of acute cocaine ad- ministration revealed widespread activation in various corti- cal and subcortical brain regions, and the temporal course (Fig.
A recent report (37) describes results 1 knockout mice demonstrated a diminished anxiogenic re- from a phase II bupropion 150 mg with amex depression websites, open-label generic bupropion 150mg depression glass defined, dose-escalating trial in which sponse on the elevated plus maze and decreased ACTH 20 severely depressed (Hamilton Depression Score 25) and corticosterone responses to restraint stress (25) order bupropion 150mg mastercard natal depression definition. Similar patients were administered R-121919 in one of two dose findings were reported by Timpl et al. Furthermore, inactivation of 50% of the patients responded positively to treatment as the CRF-1 receptor with an antisense oligonucleotide was indicated by a reduction in the Hamilton Depression Score shown to reduce the anxiogenic effect of intraventricularly of at least 50%, and 20% were remitters (score 8). In addition, no significant untoward side ity from CRF-1 antisense that was chronically infused into effects were reported, and basal or stress-induced levels of the central nucleus of the amygdala, an area of the limbic ACTH or cortisol where unaffected, suggesting that chronic system shown by Michael Davis, Joe LeDoux, and others blockade of the HPA axis might not necessarily produce to be important in mediating fear and anxiety processes. Although these preliminary data are Finally, CRF-2 knockout mice showanxiety-like behavior promising, it is important to bear in mind that they were and are hypersensitive to stress (28), indicating that the gathered using an open label design without placebo con- CRF-2 receptor has an opposite functional role to that of trol. Firm conclusions regarding the efficacy and safety of the CRF-1 receptor. Thus, it could be argued that CRF-2 CRF-1 antagonists in depression and anxiety will require agonists, rather than antagonists, might be potentially useful more rigorous double-blind, placebo-controlled trials. Several lines of evidence suggest that ences has announced that further candidates are being pur- during the period of withdrawal from drugs of abuse such sued for clinical evaluation. Anxiety is among the many physical have not been described, though recently, nonpeptide dual symptoms of drug withdrawal, and given the link that has antagonists of CRF-1 and CRF-2 receptors have been de- been made between CRF and anxiety, it is not surprising scribed (19). As there is contradictory evidence regarding that CRF-1 receptor knockout mice demonstrated de- the role of CRF-2 receptors in mediating anxiety, careful creased anxiety responses during withdrawal from alcohol preclinical and clinical evaluation of these compounds will (26). Current Drugs in Development A number of nonpeptidic, small-molecule compounds that Future Drugs and Directions showhigh selectivity for the CRF-1 receptor have been pro- posed for the treatment of depression, anxiety, and stress As indicated above, a number of drug companies have dedi- disorders (29–31). These include CP-154,526 (Pfizer), and cated significant efforts to identifying potent and selective a methylated analogue, antalarmin (Pfizer); SC 241 (Du- CRF-1 receptor antagonists suitable for clinical develop- pont); NBI 30775 (aka R-121919; Janssen-Neurocrine); ment. To date, no compounds have completed phase II and CRA 1000 and CRA 1001 (Taisho Pharmaceuticals). Clearly, a challenge for the future will be to An extensive preclinical literature has investigated potential achieve this milestone and, in the process, validate with anxiolytic effects of these compounds. Studies using CP- carefully executed clinical trials the concept that CRF-1 re- 154,526 have demonstrated anxiolytic-like effects in some ceptor antagonists are novel anxiolytics and/or antidepres- (32–34) but not all (33,34) preclinical anxiolytic paradigms sants. Also, given increasing evidence of the importance of evaluated. CP-154,526 produces an anxiolytic It will be of interest to determine if agonists, rather than effect in the separation-induced vocalization assay (35), an antagonists, of the CRF-2 receptor have anxiolytic profiles. At (BENZODIAZEPINES AND RELATED DRUGS) present, almost 20 different cDNAs have been identified and classified into six classes based upon sequence homol- A majority of the synapses in the mammalian CNS use the ogy. Cloned from vertebrates, there are six , four , four amino acids l-glutamic acid, glycine, or -aminobutyric acid , one , one , and two subunits and some splice variants; (GABA) for signaling. GABA is formed by the decarboxyl- the subunits share a basic motif where the amino acids span ation of l-glutamate, stored in neurons, and released, and the membrane four times. Because of these findings, it has Extensive mutagenesis and structural examination has been accepted for over 20 years that GABA fulfills the char- been carried out with the GABA and acetylcholine family acteristics of a neurotransmitter (38). Acetylcholine receptors have been mate, acetylcholine, and serotonin, GABA possesses two shown to possess a pentameric subunit structure with a het- different types of receptor conserved across different species erogeneous subunit composition; evidence for this conclu- and phyla that control both excitation and inhibition. Similar sion (ionotropic) and metabolism (metabotropic) are electron microscopic analysis of GABAA receptors has been mediated by proteins in two different superfamilies. It is thought that the native GABAA recep- first superfamily (GABA receptors) is a set of ligand-gated tors also possess such a pentameric structure with general A ion channels (ligand-gated superfamily) that convey composition of 2 ,2 , and one subunit forming the majority of the GABAA receptors in vertebrates. When a of this has been more circumstantial, generated by molecular GABAA receptor is activated, an ion channel is opened biological and pharmacologic inferences, described below, (gated) and this allows chloride to enter the cell; the usual and by the behavior of solubilized recombinant complexes result of chloride entry is a slowing of neuronal activity on sucrose gradient centrifugation in the presence and ab- through hyperpolarization of the cell membrane potential. Through their activity quence forms the actual ion channel of acetylcholine recep- on other effector systems, G proteins can change second tors, and that mutations of amino acids at the inner (cellu- messenger levels, altering signal transduction and gene lar) side of the membrane are responsible for the ability of expression, or open ion channels that are dependent on specific cation ions to pass through the channel pore (48). Both excitatory and The ionic selectivity can be changed by altering the charge inhibitory activities are possible on a time scale that is longer of some of these specific amino acids, and the acetylcholine than GABAA receptor mediated events. There is extensive receptor can be forced to gate chloride, rather than sodium, heterogeneity in the structure of the GABAA receptor mem- by such changes. Thus, a relatively firm case for the involve- bers of the ligand-gated superfamily. These receptors are ment of this spanning region in the formation of the ion the targets of a number of widely used and prescribed drugs channel can be made. Because the core ion pore is highly for sleep, anxiety, seizure disorders, and cognitive enhance- conserved among the large number of GABA receptor sub- A ment; they may also contribute to mediating the effects of types, a number of drugs that interact nonspecifically with ethanol on the body. These include anesthetic barbiturates, picro- Structure and Molecular Pharmacology toxin, neurosteroids, and some organic insecticides of GABA Receptors (42–44).
A practical method for grading the cognitive state of patients for the clinician purchase generic bupropion on line depression of 1929. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies cheap 150mg bupropion otc bipolar depression psychotic symptoms. Evaluation of a mental test score for assessment of mental impairment in the elderly buy bupropion american express economic depression history definition. The prevalence and incidence of Dementia with Lewy Bodies. The prevalence and incidence of Frontotemporal Dementia. Periventricular and subcortical hyperintensities on magnetic resonance imaging. Spatial distribution of cerebral white matter lesions predicts progression to mild cognitive impairment and dementia. International Journal of Geriatric Psychiatry 2009; 24:437-442. Rodriguez-Sanchez E, Mora-Simon S, Patino-Alonso M, et al. Prevalence of cognitive impairment in individuals aged over 65 in an urban area: DERIVA study. Vascular dementia: diagnosis, management and possible prevention. Racial differences in cognitive decline in a sample of community-dwelling older adults: the mediating role of education and literacy. Treating the full spectrum of dementia with memantine. Until recent decades the prefrontal areas were referred to as the “silent areas”, because injury to these regions was not accompanied by sensorimotor signs, and the function of these areas was not clear. The connections of the frontal lobes have now been described (Goldman-Rakic, 1987) and their functions have received much attention (Alvarez & Emory, 2006). The frontal lobe cortex forms a part of the frontal-subcortical circuits (these have been described in detail in Chapter 2). There are 5 parallel, separate circuits (Alexander et al, 1986). In brief, each circuit has a “direct” and an “indirect” route. The direct route has 4 components and is schematically represented: The indirect routes are a little more complicated, with a projection from the globus pallidus to the subthalamic nucleus, and another returning from the subthalamic nucleus to the globus pallidus. These 5 separate circuits form essentially closed loops, however, they receive input from other brain regions. Thus, lesions at various sites, both within the closed loops and outside, may have similar clinical effects. The motor circuit and the oculomotor unit are of importance, but of greater interest to neurology than psychiatry. The dorsolateral prefrontal, anterior cingulate and orbitofrontal circuits are of great interest to psychiatry. In the following paragraphs, the “functional regions of the frontal lobes” are discussed. The intention is to dispel the notion that the frontal lobes are the “silent areas” of the brain, and illustrate that they can be examined, at least to some extent, by an interested doctor. While there are 5 frontal-subcortical circuits, there are 6 functional regions listed below. This is because the motor and premotor frontal regions both contribute to the motor frontal-subcortical circuit. Supplementary motor area and anterior cingulated gyrus area a. Primary motor cortex The primary motor cortex or precentral gyrus (bounded posteriorally by the central sulcus) is Brodmann area 4. Although designated a “motor” cortex, this area is also involved with somatosensory perception. Lesions in this area of cortex or the subcortical elements of the associated circuit result in weakness and incoordination. Strength should be roughly equal, with greater strength on the dominant side.